小柯机器人

美国普林斯顿大学Joshua D. Rabinowitz课题组发现原发实体瘤中缓慢的三羧酸（TCA）通量和ATP产生。相关论文于2023年2月1日在线发表在《自然》杂志上。

研人员优化了示踪剂灌输方法，用于测量健康小鼠组织、Kras突变实体肿瘤、转移和白血病中的糖酵解率和TCA循环。然后，已知这两种途径的速率，研究人员计算出总ATP合成速率。结果表明，TCA循环通量在所有五种原发实体瘤模型中均被抑制，而在乳腺癌肺转移中相对于原发原位瘤增加。

正如预期的那样，与健康组织相比，肿瘤中糖酵解通量增加（Warburg效应），但这一增加不足以弥补ATP产生方面TCA低通量。它们不像通常认为的那样是高代谢的，实体瘤通常以比正常速度更慢的速度产生ATP。在小鼠胰腺癌中，这是由蛋白质合成的下调调节的，蛋白质合成是该组织的主要能量消耗之一。研究人员提出，随着实体瘤的发展，癌细胞会失去能量昂贵的组织特异性功能，尽管产生ATP的能力有限，但仍能不受控制地生长。

据了解，组织从两个途径获得ATP：糖酵解和TCA循环。哺乳动物的大部分能量是通过TCA代谢产生的。然而，在肿瘤中，这些途径的绝对比率仍然不清楚。

附：英文原文

Title: Slow TCA flux and ATP production in primary solid tumours but not metastases

Author: Bartman, Caroline R., Weilandt, Daniel R., Shen, Yihui, Lee, Won Dong, Han, Yujiao, TeSlaa, Tara, Jankowski, Connor S. R., Samarah, Laith, Park, Noel R., da Silva-Diz, Victoria, Aleksandrova, Maya, Gultekin, Yetis, Marishta, Argit, Wang, Lin, Yang, Lifeng, Roichman, Asael, Bhatt, Vrushank, Lan, Taijin, Hu, Zhixian, Xing, Xi, Lu, Wenyun, Davidson, Shawn, Whr, Martin, Vander Heiden, Matthew G., Herranz, Daniel, Guo, Jessie Yanxiang, Kang, Yibin, Rabinowitz, Joshua D.

Issue&Volume: 2023-02-01

Abstract: Tissues derive ATP from two pathways—glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue’s major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

DOI: 10.1038/s41586-022-05661-6

Source: https://www.nature.com/articles/s41586-022-05661-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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